Lung cancer is the leading cause of cancer-related mortality in China and the world, wherein non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, accounts for the majority of all cases. More specifically, NSCLC is the dominate type of lung cancer with about 85% among all lung cancers.
Over the past decade, it has become evident that subtypes of NSCLC can be further defined at the molecular level by recurrent “driver mutations” that occur in oncogenes like tyrosine kinases. There are more than 90 kinds of receptor tyrosine kinases which are related to NSCLC. EGFR mutations represent the most common type of driver mutations for NSCLC. It is assumed that about 10% Caucasian patients and 30-40% East Asian patients with NSCLC harbor EGFR mutations increasing the activity of EGFR leading to hyperactivation of the signaling pathways downstream to EGFR (e.g. Cross, D. A. et al., Cancer Discovery, 2014, 4(9):1046-1061).
EGFR belongs to a family of receptor tyrosine kinases, namely the ErbB family, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her3 (ErbB-3) and Her4 (ErbB-4) (Zhang H, et al., J. Clin. Invest. 117 (August 2007) (8): 2051-2058). EGFR is located on the surface of the cells and is activated by binding of specific ligands and dimerization, which stimulates its intrinsic intracellular protein-tyrosine kinase activity and anti-apoptotic and growth-stimulating pathways downstream to EGFR involving, for example, the phosphoinositide 3-kinase (PI3K)-AKT pathway, the STAT pathway and the MAPK pathway. This includes transautophosphorylation of some tyrosine (Y) residues in the C-terminal domain of EGFR, which include Y992, Y1045, Y1068, Y1148 and Y1173 (Herbst R S (2004). Int. J. Radiat. Oncol. Biol. Phys. 59 (2 Suppl): 21-6. doi:10.1016/j.ijrobp.2003.11.041. PMID 15142631, Tam I. Y. et al., Molecular Cancer Therapeutics, 2009, 8(8):2142-51).
Modern technology has highly improved the efficacy of treatments in NSCLC, but new challenge comes up, such as chemo-resistance and cancer relapse (Mulshine, J. L., Lung Cancer, 2003, 41 suppl 1(2):S163-74, Dragnev, K. et al., Expert Opinion on Investigational Drugs, 2013, 22(1):35-47).
The majority of EGFR mutations are non-overlapping with other mutations found in NSCLC like KRAS mutations, ALK rearrangement and the like. Some of the EGFR mutations do not reduce or increase the efficacy of EGFR inhibitors (tyrosine kinase inhibitors (TKI) of EGFR) like gefitinib, erlotinib or afatinib (Oda, K. et al., Mol. Syst. Biol. 1 (1): 2005.0010. doi:10.1038/msb4100014. PMC 1681468. PMID 16729045, Cross, D. A. et al., Cancer Discovery, 2014, 4(9):1046-1061). Other mutations reduce the efficacy of EGFR inhibitors or prevent them from working, i.e. are associated with a resistance against the EGFR inhibitor(s). An example is the T790M substitution, a point mutation in exon 20 of EGFR, as one of the mechanisms of resistance against EGFR inhibitors. There are some similar mutations associated with a resistance against EGFR inhibitors, which are D761Y, L747S and T854A etc (Li, D et al., Oncogene, 2008, 27(34):4702-4711).
A large number of clinical trials and the NCCN guidelines recommend EGFR inhibitors in patients with EGFR mutations associated with efficacy or increased efficacy of EGFR inhibitors. Although preclinical studies have shown encouraging results, resistant clinical research is not satisfactory (Jackman, D. M. et al., Clin. Cancer Res. (August 2009) 15 (16): 5267-73. doi:10.1158/1078-0432.CCR-09-0888, PMC 3219530. PMID 19671843). This is because a lot of such patients have or have developed a resistance against EGFR inhibitors in particular due to an acquired T790M mutation and/or MET gene amplification or other mechanisms. Thus, mutations usually associated with an efficacy and/or increased efficacy of EGFR inhibitors often show acquired resistance against EGFR inhibitors and patients who initially responded to EGFR inhibitors might eventually experience disease progression despite continued treatment.
Accordingly, the efficacy of EGFR inhibitors in EGFR-dependent NSCLC is limited in an increasing number of patients. Thus, further potent treatment options for treating EGFR-dependent NSCLC are urgently required. As usual, it would generally be desirable to provide treatment options including compounds with reduced risk for side effects and interactions, which compounds can be prepared in a cost-effective way. Usually, plants and respective ingredients in plants are suitable to provide such advantageous properties and, thus, research also focuses on such materials.
For example, Zi Cao, the dried root of Arnebia euchroma, Arnebia guttata, or Lithospermum erythrorhizon is already used as a Traditional Chinese medicine with the major component shikonin. The latter possesses antioxidant effects (Assimopoulou, A. N. et al., Food Chemistry (2004) 87 (3): 433-438. doi:10.1016/j.foodchem.2003.12.017), antimicrobial effects against Staphylococcus aureus and Staphylococcus epidermidis, wound healing, antitumor, and antithrombotic properties (Papageorgiou, V. P. et al., Angew. Chem. Int. Ed. (1999) 38 (3): 270-300. doi:10.1002/(SICI)1521-3773(19990201)38:3<270:AID-ANIE270>3.0.CO; 2-0). Shikonin has been shown to have anti-cancer activity such as in prostate cancer, liver cancer or breast cancer and other cancer cells, but have not been proposed for NSCLC and the specific patent group with EGFR-dependent NSCLC, respectively.